Synthesis of 8-[18F]fluoroguanine derivatives: in vivo probes for imaging gene expression with positron emission tomography

https://doi.org/10.1016/S0969-8051(99)00095-5Get rights and content

Abstract

A new method for the preparation of 8-[18F]fluoroguanine derivatives based on a direct radiofluorination reaction has been developed. The radiofluorination of ganciclovir (1a) with [18F]F2 was carried out in absolute ethanol in the presence of tetraethylammonium hydroxide at room temperature to give 8-[18F]fluoroganciclovir (3a) in an approximately 1% radiochemical yield. Similarly, 8-[18F]fluoropenciclovir (3b), 8-[18F]fluoroacyclovir (3c), and 8-[18F]fluoroguanosine (3d) were synthesized from penciclovir (1b), acyclovir (1c), and guanosine (1d), respectively, using [18F]F2. The structural analyses of the final products (3a, 3b, 3c, and 3d) were carried out after 18F decay by 1H, 13C, and 19F nuclear magnetic resonance and high resolution mass spectroscopy.

Introduction

Gene therapy based treatment of cancer related diseases is a novel and useful concept. In this strategy, tumor cells are selectively targeted and destroyed through the delivery and expression of foreign genes into malignant cells. These contrived genes convert relatively nontoxic prodrugs into metabolites that are toxic to the malignant cells. A typical example of this methodology is the gene therapy approach with herpes simplex virus type-1 thymidine kinase gene (HSV1-tk), one of the most widely used systems in tumor models (9). The HSV1-tk gene expresses high levels of the enzyme thymidine kinase (HSV1-TK), which monophosphorylates acycloguanosines 8, 11, 25. The acycloguanosine monophosphates are subsequently converted to their corresponding triphosphates by the host endogenous cellular kinases 8, 18, 26. Incorporation of the acycloguanosine triphosphate into the host DNA induces chain termination and cell death 8, 11. At the tracer level, this methodology based on the HSV1-tk gene mediated expression of the phosphorylating enzyme (HSV1-TK) allows the in vivo determination of the gene expression, as recently exemplified with the use of 3H, 14C, and 18F-labeled acyclovir, ganciclovir, and penciclovir 6, 13, 14, 15. Radioiodine labeled pyrimidine nucleosides 20, 21, 27, 28, 29 as well as purine nucleosides labeled with 18F in the acyclochain 1, 2, 19 have recently been prepared and successfully utilized in studies related to HSV1-tk gene expression, attesting to the interest in this new and rapidly developing field 13, 22. The utility of acycloguanosines as probes for imaging gene expression is based on three appealing attributes: 1) very low phosphorylation rates by mammalian thymidine kinase 3, 10, 2) excellent in vivo stability 12, 23, and 3) low host toxicity 10, 12, 23.

Based on a new approach developed in our laboratories for a selective C-8 fluorination of purines with elemental fluorine 4, 5, 6 we have now extended this procedure for the synthesis of 8-[18F]fluoroacycloguanosines. Described in this article are the synthesis of 8-[18F]fluoroganciclovir, 8-[18F]fluoropenciclovir, 8-[18F]fluoroacyclovir, and 8-[18F]fluoroguanosine as examples of a general method for the synthesis of 8-[18F]fluoroguanine derivatives.

Section snippets

General

The 1H and 19F nuclear magnetic resonance (NMR) spectra were recorded on a Bruker (Billerica, MA USA) AM-360 WB spectrometer. The 13C NMR data were collected on a Bruker ARX-500 spectrometer. The 1H and 13C chemical shifts were referenced to internal tetramethylsilane (TMS), whereas the 19F chemical shifts were referenced to an external fluorotrichloromethane standard. Fast atom bombardment (FAB) and electron impact (EI) high-resolution mass spectra (HRMS) were obtained on a ZAB SE mass

Results and discussion

A simple and regioselective procedure for fluorination of purine nucleosides at carbon-8 with elemental fluorine has recently been reported from our laboratories 4, 5, 6. This technique has been extended, in this report, to the synthesis of 8-fluoro-9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (2a, 8-fluoroganciclovir), 8-fluoro-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (2b, 8-fluoropenciclovir), and their corresponding radiolabeled analogs 8-[18F]fluoroganciclovir (3a) and 8-[18

Acknowledgements

We thank the UCLA Biomedical Cyclotron staff for their help.

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    This work was supported by Department of Energy contract DE-FC03-87ER60615.

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